The mammalian nose, with its capacity to detect millions of different odors, is an exquisite sensor of the external environment. For most animals, the sense of smell is essential for locating food, avoiding harm, navigating, and communicating between individuals. The family of olfactory receptors (ORs) responsible for the molecular recognition of odors is remarkable for its size, diversity, genomic distribution, evolutionary dynamics, and unusual regulatory control. With well over 1000 genes and occupying approximately 1% of nuclear DNA, the OR 'subgenome' provides a unique and challenging opportunity to study the evolutionary processes that shape genomes. The overall goal of this project is to understand how these processes participate in the evolution of the OR gene family, ultimately allowing animals to adapt to changing olfactory landscapes. Towards that goal, we combine computational and experimental approaches in order to globally characterize OR gene evolution, variation, and regulation. In Aim 1, we examine the selective pressures that have influenced OR evolution in multiple species. Complementary functional studies of odor recognition and neuronal wiring will further our understanding of how conservation and variation in OR gene sequences translate into olfactory perception. In Aim 2, we examine how duplication and gene conversion have led to expansion and diversification of the OR family and contribute to genotypic variation within and between species. In Aim 3, we use microarray technology to characterize the expressed repertoire of ORs, identifying additional tissues in which ORs are expressed, and how expression patterns change during development, aging, and under different environmental and physiological conditions. Finally, in Aim 4, we combine mouse genetics and genome analyses to gain new insights into the regulatory mechanisms that determine how olfactory sensory neurons select a single gene from the entire OR repertoire for expression. Together, these interrelated and complementary studies address fundamental questions in the fields of olfaction and neurobiology, while also contributing significantly to the areas of gene-family evolution, transcriptional regulation, and the origin and consequences of complex genome architectures.